One of the most common cancers in the worldUS: 4th most common cancer (after lung, prostate, and breastcancers) 2nd most common cause of cancerdeath (after lung cancer)2001: 130,000 new cases of CRC 56,500 deathscaused by CRC
Colon cancers result from a series of pathologic changes thattransform normal epithelium into invasive carcinoma. Specificgenetic events, shown by vertical arrows, accompany thismultistep process.
WHO Classification of CRCAdenocarcinoma in situ / severe dysplasiaAdenocarcinomaMucinous (colloid) adenocarcinoma (>50%mucinous)Signet ring cell carcinoma (>50% signet ringcells)Squamous cell (epidermoid) carcinomaAdenosquamous carcinomaSmall-cell (oat cell) carcinomaMedullary carcinomaUndifferentiated Carcinoma
Risk factors for CRCAgeAdenomas, PolypsSedentary lifestyle, Diet, ObesityFamily History of CRCInflammatory Bowel Disease (IBD)Hereditary Syndromes (familialadenomatous polyposis (FAP))
Development of CRCResult of interplay between environmental andgenetic factors Central environmental factors: Diet and lifestyle 35% of all cancers are attributable to diet 50%-75% of CRC in the US may be preventablethrough dietary modifications
Dietary factors implicated in colorectal carcinogenesis consumption of red meat animal and saturatedIncreased risk fat refined carbohydrates alcohol
Specimen containing an invasive colorectal carcinoma andtwo adenomatous polyps.
Multiple adenomatous polyps of the cecum are seen here in acase of familial polyposis.
Familial polyposis in which mucosal surface of the colon is acarpet of small adenomatous polyps. Even though they are small ,there is a 100% risk over time for development ofadenocarcinoma, for which total colectomy is recommended
Adenocarcinoma of the rectosigmoid region . Heaped up marginof tumor at each side with a central area of ulceration. Normalmucosa at the right. The tumor encircles the colon and infiltratesinto the wall. Staging is based upon the degree of invasion into
Adenocarcinoma of the cecum demonstrates an exophytic growthpattern.
The barium enema instills the radiopaque barium sulfate into the colon,producing a contrast with the wall of the colon that highlights any massespresent. In this case, the classic "apple core” lesion is present, representing anencircling adenocarcinoma that constricts the lumen.
Staging of CRC TNM system Primary tumor (T) Regional lymph nodes (N) Distant metastasis (M)*Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.**Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum.
Dukes staging systemA Mucosa 80%B Into or through M. propria50%C1 Into M. propria, + LN !40%C2 Through M. propria, + LN!12%D distant metastatic spread <5%
Sites of metastasisVia blood Via lymphatics Per continuitatem Liver Abdominal wall Lung Lymph nodes Nerves Brain Vessels Bone
TherapySurgical resection the only curativetreatmentLikelihood of cure is greater when diseaseis detected at an early stageEarly detection and screening is of pivotalimportance
Surgery is the mainstay of treatment of RCAfter surgical resection, local failure is commonLocal recurrence after conventional surgery:15%-45% (average of 28%)Radiotherapy significantly reduces the numberof local recurrences in rectal cancers, its use incolon cancer is not routine due to the sensitivityof the bowels to radiation.
Radiotherapy in the management of Rectal Cancer In at least 28 randomised trials the value of either preoperative or postoperative RT has been tested Preoperative RT (30+Gy): 57% relative reduction of local failure Postoperative RT (35+Gy): 33% relative reductionColorectal Cancer Collaborative Group. Lancet 2001;358:1291Gamma C. JAMA 2000;284:1008
Adjuvant Therapy of Rectal Cancer1990 US NIH Consensus ConferencePostoperative chemoradiotherapy =standard of care for RC Stage II,IIIThe consensus statement was basedupon the results of three randomised trials
ESMO RecommendationsResectable casesSurgical procedure: TMEPreoperative RT: recommendedPostoperative chemoradiotherapy: T3,4 orN+Non-resectable cases: local recurrencesPreoperative RT with or without CT
Predicting risk of recurrence in Rectal CarcinomaSurgery-related Tumor-related-Low anterior resection -Anatomic location-Excision of the -Histologic typemesorectum -Tumor grade-Extend of -Pathologic stagelymphadenectomy -radial resection-postoperative marginanastomotic -neural, venous, leakage lymphatic invasion-Tumor perforation
Incidence of local failure in RCT1-2,No,Mo <10%T3,No,Mo 15-35%T1,N1,Mo 15-35%T3-4,N1-2,Mo 45-65%
Total Mesorectal Excision (TME) Local recurrence rates after surgical resection of RC have decreased from about 30% to < 10%1. Radio(chemo)therapy2. Importance of circumferential margin (TME)
ScreeningWhat is screening?A public health service in which members of adefined population are examined to identifythose individuals who would benefit fromtreatmentTo benefit: to reduce the risk of a disease or itscomplications
Types of ScreeningFecal occult blood test (FOBT)Chemical test for blood in a stool sample.Annual screening by FOBT reducescolorectal cancer deaths by 33%Flexible sigmoidoscopy can detect about65%–75% of polyps and 40%–65% ofcolorectal cancers.Rectum and sigmoid colon are visuallyinspected
Current Screening Guidelines Regular screening for all adults aged 50 years or older is recommendedFOBT every yearFlexible sigmoidoscopy every 5 yearsTotal colon examination by colonoscopy every 10 years or by barium enema every 5–10 years
Concept of differentiation is demonstrated by this smalladenomatous polyp of the colon. Note the difference in stainingquality between the epithelial cells of the adenoma at the top andthe normal glandular epithelium of the colonic mucosa below.
At high magnification,normalal epithelium at the left contrasts with theatypical epithelium of the adenomatous polyp at the right. Nuclei aredarker and more irregularly sized and closer together in theadenomatous polyp than in the normal mucosa.
Poorly differentiated neoplasm, it is difficult to tell the cell of origin.It is probably a carcinoma because of the polygonal nature of thecells. Note that nucleoli are numerous and large in this neoplasm.
CK staining reaction for carcinomas helps to distinguish carcinoma fromsarcomas and lymphomas. Immunoperoxidase staining is helpful to determinethe cell type of a neoplasm when the degree of differentiation, or morphologyalone, does not allow an exact classification.
Molecular Biology & PathologyCRCs arise from a series of histopathological and molecularchanges that transform normal epithelial cellsIntermediate step is the adenomatous polypAdenoma-Carcinoma-Sequence (Vogelstein & Kinzler)Polyps occur universally in FAP, but FAP accounts for only1% of CRCsAdenomatous Polyps in general population: 33% at age 50 70% at age 70
SummaryCRC is a leading cause of deathEarly stages are detectableScreening can prevent CRC